SMN OLIGOMERIZATION DEFECT CORRELATES WITH SPINAL MUSCULAR-ATROPHY SEVERITY

Spinal muscular atrophy (SMA) is a motor-neuron disorder resulting fro m anterior-horn-cell death. The autosomal recessive form has a carrier frequency of 1 in 50 and is the most common genetic cause of infant d eath. SMA is categorized as types I-III, ranging from severe to mild, based upon age of onset and clinical course. Two closely flanking copi es of the survival motor neuron (SMN) gene are on chromosome 5913 (ref . 1). The telomeric SMN (SMN1) copy is homozygously deleted or convert ed in >95% of SMA patients, while a small number of SMA disease allele s contain missense mutations within the carboxy terminus. We have iden tified a modular oligomerization domain within exon 6 of SMN1. All pre viously identified missense mutations map within or immediately adjace nt to this domain. Comparison of wild-type to mutant SMN proteins of t ype I, II and III SMA patients showed a direct correlation between oli gomerization and clinical type. Moreover, the most abundant centromeri c SMN product, which encodes exons 1-6 but not 7, demonstrated reduced self-association. These findings identify decreased SMN self-associat ion as a biochemical defect in SMA, and imply that disease severity is proportional to the intracellular concentration of oligomerization-co mpetent SMN proteins.